DESCRIPTION: The Werner syndrome (WS) ('Progeria of the Adult') is a rare autosomal recessive progeriod disorder. WS patients show a general appearance of premature aging, and exhibit premature onset of disorders commonly seen in the aged population including, bilateral ocular cataracts, type 2 diabetes mellitus, arteriosclerosis and osteoporosis. While they are susceptible to many neoplasms, these include a disproportionate number of cancers of mesenchymal origin and relatively rare neoplasms. Somatic cells from WS patients exhibit accelerated replicative senescence and a mutator phenotype. The Werner syndrome gene (WRN) has recently been shown to encode a helicase homologous to the RecQ of E. coli. Initially, four distinct mutations in the WRN gene were found in Japanese and Caucasian WS patients. Subsequently, more than a dozen different mutations have been identified. In this proposal, animal models of WS by targeted mutagenesis of the murine homolouge of WRN will be created. The goal is to create models of two naturally occurring human mutations, including the common Japanese exonic deletion. Life table parameters and anatomical pathology data, with emphasis upon analysis of the frequencies and the spectrum of neoplasms, will be obtained throughout the lifespan of C57B1/6 transgenic control mice. Primary cultures of somatic cells isolated from the transgenic mice will be used to determine replicative lifespan, WRN helicase activity levels and mutation frequencies at the HPRT locus. The long term goal is to elucidate the pathogenesis of WS and the role of WRN helicase in normal aging.